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Three dimensions of the amyloid hypothesis: time, space and 'wingmen'

Abstract

The amyloid hypothesis, which has been the predominant framework for research in Alzheimer's disease (AD), has been the source of considerable controversy. The amyloid hypothesis postulates that amyloid-β peptide (Aβ) is the causative agent in AD. It is strongly supported by data from rare autosomal dominant forms of AD. However, the evidence that Aβ causes or contributes to age-associated sporadic AD is more complex and less clear, prompting criticism of the hypothesis. We provide an overview of the major arguments for and against the amyloid hypothesis. We conclude that Aβ likely is the key initiator of a complex pathogenic cascade that causes AD. However, we argue that Aβ acts primarily as a trigger of other downstream processes, particularly tau aggregation, which mediate neurodegeneration. Aβ appears to be necessary, but not sufficient, to cause AD. Its major pathogenic effects may occur very early in the disease process.

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Figure 1: An updated framework of the amyloid hypothesis.

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Acknowledgements

E.S.M. is supported by NINDS grant K08NS079405 and Alzheimer's Association grant NIRG-305476. D.M.H. is supported by NIH grants R01 NS090934, R01 AG047644, P01 NS074969, P01 NS080675, PO1-AG03991, R01 NS034467, P01-AG026276, and U01 AG032438 and from the Tau Consortium and Cure Alzheimer's Fund.

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Correspondence to David M Holtzman.

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D.M.H. is a co-founder of C2N Diagnostics, LLC, a member of the scientific advisory board of C2N Diagnostics, and a consultant for Genentech, AstraZeneca, Neurophage and Eli Lilly. Washington University receives grants for the laboratory of D.M.H. from C2N Diagnostics, Eli Lilly and Janssen.

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Musiek, E., Holtzman, D. Three dimensions of the amyloid hypothesis: time, space and 'wingmen'. Nat Neurosci 18, 800–806 (2015). https://doi.org/10.1038/nn.4018

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